1. Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease.
- Author
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Vilariño-Güell C, Zimprich A, Martinelli-Boneschi F, Herculano B, Wang Z, Matesanz F, Urcelay E, Vandenbroeck K, Leyva L, Gris D, Massaad C, Quandt JA, Traboulsee AL, Encarnacion M, Bernales CQ, Follett J, Yee IM, Criscuoli MG, Deutschländer A, Reinthaler EM, Zrzavy T, Mascia E, Zauli A, Esposito F, Alcina A, Izquierdo G, Espino-Paisán L, Mena J, Antigüedad A, Urbaneja-Romero P, Ortega-Pinazo J, Song W, and Sadovnick AD
- Subjects
- Adult, Codon, Nonsense, Demyelinating Diseases genetics, Demyelinating Diseases pathology, Exome genetics, Female, Humans, Inflammation metabolism, Inflammation pathology, Male, Middle Aged, Multiple Sclerosis metabolism, Multiple Sclerosis pathology, Myelin Sheath genetics, Myelin Sheath pathology, Nerve Degeneration genetics, Nerve Degeneration pathology, Neurons metabolism, Neurons pathology, Pedigree, Exome Sequencing, Young Adult, Genetic Predisposition to Disease, Inflammation genetics, Multiple Sclerosis genetics, Transcriptome genetics
- Abstract
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by myelin loss and neuronal dysfunction. Although the majority of patients do not present familial aggregation, Mendelian forms have been described. We performed whole-exome sequencing analysis in 132 patients from 34 multi-incident families, which nominated likely pathogenic variants for MS in 12 genes of the innate immune system that regulate the transcription and activation of inflammatory mediators. Rare missense or nonsense variants were identified in genes of the fibrinolysis and complement pathways (PLAU, MASP1, C2), inflammasome assembly (NLRP12), Wnt signaling (UBR2, CTNNA3, NFATC2, RNF213), nuclear receptor complexes (NCOA3), and cation channels and exchangers (KCNG4, SLC24A6, SLC8B1). These genes suggest a disruption of interconnected immunological and pro-inflammatory pathways as the initial event in the pathophysiology of familial MS, and provide the molecular and biological rationale for the chronic inflammation, demyelination and neurodegeneration observed in MS patients., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2019
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